Geographic Disparities in Liver Availability: Accidents of Geography, or Consequences of Poor Social Policy?

Recently, a redistricting proposal intended to equalize Model for End-stage Liver Disease score at transplant recommended expanding liver sharing to mitigate geographic variation in liver transplantation. Yet, it is unclear whether variation in liver availability is arbitrary and a disparity requiring rectification or reflects differences in access to care. We evaluate the proposal's claim that organ supply is an "accident of geography" by examining the relationship between local organ supply and the uneven landscape of social determinants and policies that contribute to differential death rates across the United States. We show that higher mortality leading to greater availability of organs may in part result from disproportionate risks incurred at the local level. Disparities in public safety laws, health care infrastructure, and public funding may influence the risk of death and subsequent availability of deceased donors. These risk factors are disproportionately prevalent in regions with high organ supply. Policies calling for organ redistribution from high-supply to low-supply regions may exacerbate existing social and health inequalities by redistributing the single benefit (greater organ availability) of greater exposure to environmental and contextual risks (e.g. violent death, healthcare scarcity). Variation in liver availability may not be an "accident of geography" but rather a byproduct of disadvantage.

A genomic case study of mixed fibrolamellar hepatocellular carcinoma.

BACKGROUND: Mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) is a rare liver tumor defined by the presence of both pure FL-HCC and conventional HCC components, represents up to 25% of cases of FL-HCC, and has been associated with worse prognosis. Recent genomic characterization of pure FL-HCC identified a highly recurrent transcript fusion (DNAJB1:PRKACA) not found in conventional HCC. PATIENTS AND METHODS: We performed exome and transcriptome sequencing of a case of mFL-HCC. A novel BAC-capture approach was developed to identify a 400 kb deletion as the underlying genomic mechanism for a DNAJB1:PRKACA fusion in this case. A sensitive Nanostring Elements assay was used to screen for this transcript fusion in a second case of mFL-HCC, 112 additional HCC samples and 44 adjacent non-tumor liver samples. RESULTS: We report the first comprehensive genomic analysis of a case of mFL-HCC. No common HCC-associated mutations were identified. The very low mutation rate of this case, large number of mostly single-copy, long-range copy number variants, and high expression of ERBB2 were more consistent with previous reports of pure FL-HCC than conventional HCC. In particular, the DNAJB1:PRKACA fusion transcript specifically associated with pure FL-HCC was detected at very high expression levels. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed our finding that the fusion was detectable in conventional components. An expanded screen identified a third case of fusion-positive HCC, which upon review, also had both conventional and fibrolamellar features. This screen confirmed the absence of the fusion in all conventional HCC and adjacent non-tumor liver samples. CONCLUSION: These results indicate that mFL-HCC is similar to pure FL-HCC at the genomic level and the DNAJB1:PRKACA fusion can be used as a diagnostic tool for both pure and mFL-HCC.

A consolidated biovigilance system for blood, tissue and organs: one size does not fit all.

Biovigilance systems to assess and analyze risks for disease transmission through the transfer of organs, tissue, cells and blood between people is part of administrative oversight and has impact upon clinical practice and policy. In 2009, a formal recommendation by the Public Health Service requested that Health and Human Services fund and support efforts to consolidate national biovigilance efforts. There are differences in the biovigilance issues involved in organ and tissue donation/transplantation. If disease avoidance is made the dominant principle guiding organ donor testing, an unintended consequence may be an increase in deaths on the waiting list. We propose that overall benefit for the organ transplant recipient, tempered by patient informed awareness of limited organ availability and assessment processes, should be the guiding principle of such a system.

Rational rationing or discrimination: balancing equity and efficiency considerations in kidney allocation.

After 6 years of deliberation, the Organ Procurement and Transplantation Network recently released a concept document proposing changes to the kidney allocation algorithm, sparking a heated debate about priority-setting of scarce health resources and discrimination. Proponents of the proposal argue that it will result in an additional 15,223 life years following transplant annually for recipients, yet the benefit will not be equally distributed and will likely benefit younger patients. Critics argue that the new model will promote age discrimination and may lead to a further decrease in live kidney donation. If true, these concerns could undermine fairness and damage public trust in the organ allocation system. We address these objections and consider their merit, highlighting both benefits and shortcomings of the proposal. We argue that, despite weaknesses of the proposal and the importance of maintaining consistency in patient and provider expectations over time, the proposal represents a needed first step in balancing equity and efficiency.

Patients' willingness to accept expanded criteria donor liver transplantation.

Utilization of livers from expanded criteria donors (ECD) is one strategy to overcome the severe organ shortage. The decision to utilize an ECD liver is complex and fraught with uncertainty for both providers and patients. We assessed patients' willingness to accept ECD liver transplantation (LTx) and acceptable 1-year mortality risk. One hundred eight patients listed for LTx were asked to rate their willingness to accept ECD LTx and the associated 1-year mortality risk they were willing to accept. Also, patients completed the SF-36v2 and sociodemographic and health information was gathered from their medical records. Patients reported significantly higher willingness to accept standard criteria donor (SCD) versus ECD LTx (t = 13.8, p < 0.001), with more than one-third of patients reporting low willingness to accept ECD LTx. Relative to our center's 10% SCD LTx 1-year mortality rate, most patients (71%) were willing to accept moderately or substantially higher 1-year mortality risk for ECD LTx. In multivariable analyses, higher lab MELD score and white race were significant independent predictors of both ECD willingness and ECD increased mortality risk acceptability. Findings highlight the importance of assessing patients' willingness to pursue ECD LTx and the relative mortality risks they are willing to accept.

Understanding disparities in transplantation: do social networks provide the missing clue?

Although the National Organ Transplant Act calls for equity in access to transplantation, scarcity and racial disparities persist. To date, even the most comprehensive models have been unable to adequately explain these racial disparities, leaving policymakers unsure how best to intervene. Previous individual-level analyses, which have implicated risk factors such as race, financial status, cultural beliefs, unemployment, lack of commitment to surgery and lack of continuous access to care, overlook contextual and social network exposures. Social networks present a compelling way to examine cumulative risk clustered across individuals. Social networks have been shown to influence health outcomes and health behaviors through various pathways, including shared social capital, engaging in similar or group risky behaviors, diffusion of information and adopting or propagating social norms. Precursors to chronic kidney disease, including obesity, have been shown to spread through social networks. Social network analysis can reveal shared risks between potential donors and recipients in a given network, clarifying the likelihood of finding an appropriate match through either direct donation or paired exchanges. This paper presents a novel application of social network analysis to transplantation, illustrating implications for disparities and future clinical interventions.

Successful DCD kidney transplantation using early corticosteroid withdrawal.

Organs from donors after cardiac death (DCD) are being increasingly utilized. Prior reports of DCD kidney transplantation involve the use of prednisone-based immunosuppression. We report our experience with early corticosteroid withdrawal (ECSW). Data on 63 DCD kidney transplants performed between 2002 and 2007 were analyzed. We compared outcomes in 28 recipients maintained on long-term corticosteroids (LTCSs) with 35 recipients that underwent ECSW. DGF occurred in 49% of patients on ECSW and 46% on LTCS (p=0.8). There was no difference between groups for serum creatinine or estimated GFR between 1 and 36 months posttransplant. Acute rejection rates at 1 year were 11.4% and 21.4% for the ECSW and LTCS group (p=0.2). Graft survival at 1 and 3 years was 94% and 91% for the ECSW group versus 82% and 78% for the LTCS group (p>or=0.1). Death censored graft survival was significantly better at last follow-up for the ECSW group (p=0.02). Multivariate analysis revealed no correlation between the use of corticosteroids and survival outcomes. In conclusion, ECSW can be used successfully in DCD kidney transplantation with no worse outcomes in DGF, rejection, graft loss or the combined outcome of death and graft loss compared to patients receiving LTCS.

Intraoperative administration of inhaled carbon monoxide reduces delayed graft function in kidney allografts in Swine.

Ischemia/reperfusion injury and delayed graft function (DGF) following organ transplantation adversely affect graft function and survival. A large animal model has not been characterized. We developed a pig kidney allograft model of DGF and evaluated the cytoprotective effects of inhaled carbon monoxide (CO). We demonstrate that donor warm ischemia time is a critical determinant of DGF as evidenced by a transient (4-6 days) increase in serum creatinine and blood urea nitrogen following transplantation before returning to baseline. CO administered to recipients intraoperatively for 1 h restored kidney function more rapidly versus air-treated controls. CO reduced acute tubular necrosis, apoptosis, tissue factor expression and P-selectin expression and enhanced proliferative repair as measured by phosphorylation of retinol binding protein and histone H3. Gene microarray analyses with confirmatory PCR of biopsy specimens showed that CO blocked proinflammatory gene expression of MCP-1 and heat shock proteins. In vitro in pig renal epithelial cells, CO blocks anoxia-reoxygenation-induced cell death while promoting proliferation. This large animal model of DGF can be utilized for testing therapeutic strategies to reduce or prevent DGF in humans. The efficacy of CO on improving graft function posttransplant validates the model and offers a potentially important therapeutic strategy to improve transplant outcomes.

Framing disparities along the continuum of care from chronic kidney disease to transplantation: barriers and interventions.

Research in renal transplantation continues to document scores of disparities affecting vulnerable populations at various stages along the transplantation process. Given that both biological and environmental determinants contribute significantly to variation, identifying factors underlying an unfairly biased distribution of the disease burden is crucial. Confounded definitions and gaps in understanding causal pathways impede effectiveness of interventions aimed at alleviating disparities. This article offers an operational definition of disparities in the context of a framework aimed at facilitating interventional research. Utilizing an original framework describing the entire continuum of the transplant process from diagnosis of chronic kidney disease through successful transplant, this article explores the case of racial disparities, illustrating key factors predicting and perpetuating disparities. Though gaps in current research leave us unable to identify which stages of the transplant pathway adversely affect most people, by identifying key risk factors across the continuum of care, this article highlights areas suited for targeted interventions and presents recommendations for improvement and future research.

ASTS recommended practice guidelines for controlled donation after cardiac death organ procurement and transplantation.

The American Society of Transplant Surgeons (ASTS) champions efforts to increase organ donation. Controlled donation after cardiac death (DCD) offers the family and the patient with a hopeless prognosis the option to donate when brain death criteria will not be met. Although DCD is increasing, this endeavor is still in the midst of development. DCD protocols, recovery techniques and organ acceptance criteria vary among organ procurement organizations and transplant centers. Growing enthusiasm for DCD has been tempered by the decreased yield of transplantable organs and less favorable posttransplant outcomes compared with donation after brain death. Logistics and ethics relevant to DCD engender discussion and debate among lay and medical communities. Regulatory oversight of the mandate to increase DCD and a recent lawsuit involving professional behavior during an attempted DCD have fueled scrutiny of this activity. Within this setting, the ASTS Council sought best-practice guidelines for controlled DCD organ donation and transplantation. The proposed guidelines are evidence based when possible. They cover many aspects of DCD kidney, liver and pancreas transplantation, including donor characteristics, consent, withdrawal of ventilatory support, operative technique, ischemia times, machine perfusion, recipient considerations and biliary issues. DCD organ transplantation involves unique challenges that these recommendations seek to address.

Improving long-term outcomes after liver transplantation in children.

The objective was to review the current state of knowledge and recommend future research directions related to long-term outcomes for pediatric liver transplant recipients. A 1-day Clinical Research Workshop on Improving Long-Term Outcomes for Pediatric Liver Transplant Recipients was held on February 12, 2007, in Washington, DC. The speaker topics were germane to research priorities delineated in the chapters on Pediatric Liver Diseases and on Liver Transplantation in the Trans-NIH Action Plan for Liver Disease Research. Issues that compromise long-term well-being and survival but are amenable to existing and new research efforts were presented and discussed. Areas of research that further enhanced the research priorities in the Action Plan for Liver Disease Research included collection of longitudinal data to define emerging trends of clinical challenges; identification of risk factors associated with long-term immunosuppression complications; development of tolerance-inducing regimens; definition of biomarkers that reflect the level of clinical immunosuppression; development of instruments for the measurement of health wellness; identification of risk factors that impede growth and intellectual development before and after liver transplantation and identification of barriers and facilitators that impact nonadherence and transition of care for adolescents.

Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients.

The lymphoproliferative processes that developed in five renal transplant recipients were studied in an attempt to characterize and classify them morphologically. Nine surgical specimens, hematological material on all patients, and autopsy specimens from three patients were available. Studies performed included: conventional histopathology; evaluation of cell markers (immunoglobulins and sheep erythrocyte, complement, and Fc receptors) and cytoplasmic immunoglobulins (peroxidase-antiperoxidase technique); ultrastructural examination; and karyotype analysis. The lymphoid lesions in our patients shared marked cytological polymorphism (small and large cells, of both follicular center and "medullary" type) and polyclonal B-cell features, which indicated a common reactive nonneoplastic origin. However, other features, such as morphological atypia of the immunoblasts, extensive necrosis, chromosomal aberrations, and an incipient monoclonal component suggested the development of lymphoma in some of these lesions. In contradistinction, the abundance of typical immunoblasts was a feature that seemed to correlate with the clinical activity of the disease rather than with the biological malignancy. The multiplicity of B-cell types and the presence of a follicular center cell component with diffuse distribution, as well as the extensive necrosis in the malignant forms, seem to differentiate morphologically the lymphoproliferative processes arising in transplant recipients from both the hyperplasias and the lymphomas developing in immunologically normal hosts. For the former, we propose the terms of "polymorphic diffuse B-cell hyperplasias" and "polymorphic B-cell lymphomas."

Documentation of Epstein-Barr virus infection in immunodeficient patients with life-threatening lymphoproliferative diseases by Epstein-Barr virus complementary RNA/DNA and viral DNA/DNA hybridization.

Tissues from patients thought to have Epstein-Barr virus (EBV)-induced lymphoproliferative diseases were probed for EBV genomes using 2 independent hybridization techniques. Tissues from six patients with the X-linked lymphoproliferative syndrome, all five renal allograft recipients with immunoblastic sarcoma, and eight patients with diverse types of immunodeficiency and lymphoproliferative diseases such as fatal infectious mononucleosis or malignant lymphoma associated with antecedent immunodeficiency contained significant numbers of EBV genome equivalents per cell. The use of 2 hybridization probes is recommended to confirm the presence of EBV genomes. The finding of significant numbers of EBV genomes in tissues from patients with immunodeficiency suggests that EBV is the etiological agent of the associated lymphoproliferative diseases.

Clinical spectrum of lymphoproliferative disorders in renal transplant recipients and evidence for the role of Epstein-Barr virus.

Six renal transplant recipients with abnormal lymphoproliferative disorders were studied in an attempt to define their clinical features and the role of Epstein-Barr virus (EBV) in their pathogenesis. Patients were either teenage (three) or in the sixth decade (three). The younger patients presented an average of 3 months after transplantation with fever, sore throat, and lymphadenopathy; had been markedly immunosuppressed; frequently had preceding or concomitant cytomegalovirus infections; and two of three had a rapidly fatal course. The older patients presented an average of 5 years after transplantation while on maintenance immunosuppressive drugs; in two of three cases with an oropharyngeal tumor; and had a more indolent, but frequently fatal, clinical course. The most frequent sites of biopsy-proven involvement in these patients were lymph nodes (three), the oropharynx (three), liver (three), bone marrow (three), transplanted kidney (three), colon (two), and central nervous system (two). EBV-specific antibody titers including anti-viral capsid antigen IgG, anti-viral capsid antigen IgM, anti-early antigen, and anti-Epstein-Barr nuclear antigen were serially measured in all patients. Four patients demonstrated serological evidence of a primary (one) or reactivation (three) EBV infection. No patient had significant changes in anti-early antigen or anti-Epstein-Barr nuclear antigen titers. All three patients tested for oropharyngeal shedding of EBV were positive. A touch imprint of one tumor was stained for the presence of Epstein-Barr nuclear antigen, and a majority of cells were positive. EBV complementary RNA/DNA filter hybridization and/or viral DNA/DNA reassociation analysis performed on tumor biopsy specimens in five patients demonstrated multiple EBV genome equivalents per cell in all eight specimens tested. Clinical, pathological, serological, and molecular hybridization studies provide substantial evidence that EBV was the cause of these lymphoproliferative disorders occurring after renal transplantation. Impaired host defenses allow the EBV-transformed B-lymphocytes to escape normal control mechanisms. This impairment is invariable and influenced by many factors resulting in the observed spectrum of disease. Cytogenetic changes, however, may also be important.